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Clinical Reviews in Allergy & Immunology

Published in:

18-09-2021 | Cytokines

Immunology of Aging: the Birth of Inflammaging

Authors: T. Fulop, A. Larbi, G. Pawelec, A. Khalil, A. A. Cohen, K. Hirokawa, J. M. Witkowski, C. Franceschi

Published in: Clinical Reviews in Allergy & Immunology | Issue 2/2023

Abstract

The inflammaging concept was introduced in 2000 by Prof. Franceschi. This was an evolutionary or rather a revolutionary conceptualization of the immune changes in response to a lifelong stress. This conceptualization permitted to consider the lifelong proinflammatory process as an adaptation which could eventually lead to either beneficial or detrimental consequences. This dichotomy is influenced by both the genetics and the environment. Depending on which way prevails in an individual, the outcome may be healthy longevity or pathological aging burdened with aging-related diseases. The concept of inflammaging has also revealed the complex, systemic nature of aging. Thus, this conceptualization opens the way to consider age-related processes in their complexity, meaning that not only the process but also all counter-processes should be considered. It has also opened the way to add new concepts to the original one, leading to better understanding of the nature of inflammaging and of aging itself. Finally, it showed the way towards potential multimodal interventions involving a holistic approach to optimize the aging process towards a healthy longevity.

Dziechciaż M, Filip R (2014) Biological psychological and social determinants of old age: bio-psycho-social aspects of human aging. Ann Agric Environ Med 21:835–838. https://doi.org/10.5604/12321966.1129943CrossRefPubMed

Cohen AA (2016) Complex systems dynamics in aging: new evidence, continuing questions. Biogerontology 17:205–220. https://doi.org/10.1007/s10522-015-9584-xCrossRefPubMed

da Costa JP, Vitorino R, Silva GM, Vogel C, Duarte AC, Rocha-Santos T (2016) A synopsis on aging-theories, mechanisms and future prospects. Ageing Res Rev 29:90–112. https://doi.org/10.1016/j.arr.2016.06.005CrossRefPubMedPubMedCentral

Cohen AA, Kennedy BK, Anglas U, Bronikowski AM, Deelen J, Dufour F, Ferbeyre G, Ferrucci L, Franceschi C, Frasca D, Friguet B, Gaudreau P, Gladyshev VN, Gonos ES, Gorbunova V, Gut P, Ivanchenko M, Legault V, Lemaître JF, Liontis T, Liu GH, Liu M, Maier AB, Nóbrega OT, Olde Rikkert MGM, Pawelec G, Rheault S, Senior AM, Simm A, Soo S, Traa A, Ukraintseva S, Vanhaelen Q, Van Raamsdonk JM, Witkowski JM, Yashin AI, Ziman R, Fülöp T (2020) Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. Mech Ageing Dev 191:111316. https://doi.org/10.1016/j.mad.2020.111316CrossRefPubMedPubMedCentral

López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217. https://doi.org/10.1016/j.cell.2013.05.039CrossRefPubMedPubMedCentral

Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (2000) Inflamm-aging. an evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254. https://doi.org/10.1111/j.1749-6632.2000.tb06651.xCrossRefPubMed

Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A (2018) Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 14:576–590. https://doi.org/10.1038/s41574-018-0059-4CrossRefPubMed

Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 69(Suppl 1):S4-9. https://doi.org/10.1093/gerona/glu057CrossRefPubMed

Fulop T, Witkowski JM, Olivieri F, Larbi A (2018) The integration of inflammaging in age-related diseases. Semin Immunol 40:17–35. https://doi.org/10.1016/j.smim.2018.09.003CrossRefPubMed

10.

Barbé-Tuana F, Funchal G, Schmitz CRR, Maurmann RM, Bauer ME (2020) The interplay between immunosenescence and age-related diseases. Semin Immunopathol 42:545–557. https://doi.org/10.1007/s00281-020-00806-zCrossRefPubMedPubMedCentral

11.

Chung HY, Kim DH, Lee EK, Chung KW, Chung S, Lee B, Seo AY, Chung JH, Jung YS, Im E, Lee J, Kim ND, Choi YJ, Im DS, Yu BP (2019) Redefining chronic inflammation in aging and age-related diseases: proposal of the senoinflammation concept. Aging Dis 10:367–382. https://doi.org/10.14336/AD.2018.0324CrossRefPubMedPubMedCentral

12.

Royce GH, Brown-Borg HM, Deepa SS (2019) The potential role of necroptosis in inflammaging and aging. Geroscience 41:795–811. https://doi.org/10.1007/s11357-019-00131-wCrossRefPubMedPubMedCentral

13.

Minciullo PL, Catalano A, Mandraffino G, Casciaro M, Crucitti A, Maltese G, Morabito N, Lasco A, Gangemi S, Basile G (2016) Inflammaging and anti-inflammaging: the role of cytokines in extreme longevity. Arch Immunol Ther Exp (Warsz) 64:111–126. https://doi.org/10.1007/s00005-015-0377-3CrossRefPubMed

14.

Zuo L, Prather ER, Stetskiv M, Garrison DE, Meade JR, Peace TI, Zhou T (2019) Inflammaging and oxidative stress in human diseases: from molecular mechanisms to novel treatments. Int J Mol Sci 20(18):4472. https://doi.org/10.3390/ijms20184472CrossRefPubMedPubMedCentral

15.

Chen G, Yung R (2019) Meta-inflammaging at the crossroad of geroscience. Aging Med (Milton) 2:157–161. https://doi.org/10.1002/agm2.12078CrossRefPubMed

16.

Müller L, Di Benedetto S, Pawelec G (2019) The immune system and its dysregulation with aging. Subcell Biochem 91:21–43. https://doi.org/10.1007/978-981-13-3681-2_2CrossRefPubMed

17.

Pawelec G, Bronikowski A, Cunnane SC, Ferrucci L, Franceschi C, Fülöp T, Gaudreau P, Gladyshev VN, Gonos ES, Gorbunova V, Kennedy BK, Larbi A, Lemaître JF, Liu GH, Maier AB, Morais JA, Nóbrega OT, Moskalev A, Rikkert MO, Seluanov A, Senior AM, Ukraintseva S, Vanhaelen Q, Witkowski J, Cohen AA (2020) The conundrum of human immune system “senescence.” Mech Ageing Dev 192:111357. https://doi.org/10.1016/j.mad.2020.111357CrossRefPubMedPubMedCentral

18.

Xu W, Wong G, Hwang YY, Larbi A (2020) The untwining of immunosenescence and aging. Semin Immunopathol 42:559–572. https://doi.org/10.1007/s00281-020-00824-xCrossRefPubMedPubMedCentral

19.

Allen JC, Toapanta FR, Chen W, Tennant SM (2020) Understanding immunosenescence and its impact on vaccination of older adults. Vaccine 38:8264–8272. https://doi.org/10.1016/j.vaccine.2020.11.002CrossRefPubMedPubMedCentral

20.

Salminen A, Kaarniranta K, Kauppinen A (2019) Immunosenescence: the potential role of myeloid-derived suppressor cells (MDSC) in age-related immune deficiency. Cell Mol Life Sci 76:1901–1918. https://doi.org/10.1007/s00018-019-03048-xCrossRefPubMedPubMedCentral

21.

Drew W, Wilson DV, Sapey E (2018) Inflammation and neutrophil immunosenescence in health and disease: targeted treatments to improve clinical outcomes in the elderly. Exp Gerontol 105:70–77. https://doi.org/10.1016/j.exger.2017.12.020CrossRefPubMed

22.

Moskalev A, Stambler I, Caruso C (2020) Innate and adaptive immunity in aging and longevity: the foundation of resilience. Aging Dis 11:1363–1373. https://doi.org/10.14336/AD.2020.0603CrossRefPubMedPubMedCentral

23.

Nikolich-Žugich J (2018) The twilight of immunity: emerging concepts in aging of the immune system. Nat Immunol 19:10–19. https://doi.org/10.1038/s41590-017-0006-xCrossRefPubMed

24.

Solana R, Tarazona R, Gayoso I, Lesur O, Dupuis G, Fulop T (2012) Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. Semin Immunol 24:331–341. https://doi.org/10.1016/j.smim.2012.04.008CrossRefPubMed

25.

Panda A, Arjona A, Sapey E, Bai F, Fikrig E, Montgomery RR, Lord JM (2009) Shaw AC. Human innate immunosenescence: causes and consequences for immunity in old age. Trends Immunol 30:325–333. https://doi.org/10.1016/j.it.2009.05.004CrossRefPubMedPubMedCentral

26.

Bandaranayake T, Shaw AC (2016) Clin Geriatr Med 32:415–432. https://doi.org/10.1016/j.cger.2016.02.007CrossRefPubMedPubMedCentral

27.

Bektas A, Schurman SH, Sen R, Ferrucci L (2017) Human T cell immunosenescence and inflammation in aging. J Leukoc Biol 102:977–988. https://doi.org/10.1189/jlb.3RI0716-335RCrossRefPubMedPubMedCentral

28.

Goronzy JJ, Weyand CM (2019) Mechanisms underlying T cell ageing. Nat Rev Immunol 19:573–583. https://doi.org/10.1038/s41577-019-0180-1CrossRefPubMedPubMedCentral

29.

Wong GCL, Strickland MC, Larbi A (2020) Changes in T cell homeostasis and vaccine responses in old age. Interdiscip Top Gerontol Geriatr 43:36–55. https://doi.org/10.1159/000504487CrossRefPubMed

30.

Saavedra D, Fuertes SA, Suárez GM, González A, Lorenzo-Luaces P, García B, Aznar E, Mazorra Z, Crombet T, Speiser DE, Lage A (2019) Biomodulina T partially restores immunosenescent CD4 and CD8 T cell compartments in the elderly. Exp Gerontol 124:110633. https://doi.org/10.1016/j.exger.2019.110633CrossRefPubMed

31.

Alves AS, Bueno V (2019) Immunosenescence: participation of T lymphocytes and myeloid-derived suppressor cells in aging-related immune response changes. Einstein (Sao Paulo). 17(2):eRB4733. https://doi.org/10.31744/einstein_journal/2019RB4733

32.

Koch S, Solana R, Dela Rosa O, Pawelec G (2006) Human cytomegalovirus infection and T cell immunosenescence: a mini review. Mech Ageing Dev 127:538–543. https://doi.org/10.1016/j.mad.2006.01.011CrossRefPubMed

33.

Larbi A, Fulop T (2014) From “truly naive” to “exhausted senescent” T cells: when markers predict functionality. Cytometry A 85:25–35. https://doi.org/10.1002/cyto.a.22351CrossRefPubMed

34.

Hazeldine J, Lord JM (2015) Innate immunesenescence: underlying mechanisms and clinical relevance. Biogerontology 16:187–201. https://doi.org/10.1007/s10522-014-9514-3CrossRefPubMed

35.

Montgomery RR, Shaw AC (2015) Paradoxical changes in innate immunity in aging: recent progress and new directions. J Leukoc Biol 98:937–943. https://doi.org/10.1189/jlb.5MR0315-104RCrossRefPubMedPubMedCentral

36.

Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM (2010) Aging of the innate immune system. Curr Opin Immunol 22(4):507–513. https://doi.org/10.1016/j.coi.2010.05.003CrossRefPubMedPubMedCentral

37.

Fulop T, Larbi A, Douziech N, Fortin C, Guérard KP, Lesur O, Khalil A, Dupuis G (2004) Signal transduction and functional changes in neutrophils with aging. Aging Cell 3:217–226. https://doi.org/10.1111/j.1474-9728.2004.00110.xCrossRefPubMed

38.

Fülöp T Jr, Fóris G, Wórum I, Leövey A (1985) Age-dependent alterations of Fc gamma receptor-mediated effector functions of human polymorphonuclear leucocytes. Clin Exp Immunol 61:425–432PubMedPubMedCentral

39.

Fülöp T, Fóris G, Wórum I, Leövey A (1984) Age-dependent changes of the Fc gamma-receptor-mediated functions of human monocytes. Int Arch Allergy Appl Immunol 74:76–79. https://doi.org/10.1159/000233520CrossRefPubMed

40.

Tomar N, De RK (2014) A brief outline of the immune system. Methods Mol Biol 1184:3–12. https://doi.org/10.1007/978-1-4939-1115-8_1CrossRefPubMed

41.

Bonilla FA, Oettgen HC (2010) Adaptive immunity. J Allergy Clin Immunol 125(2 Suppl 2):S33-40. https://doi.org/10.1016/j.jaci.2009.09.017CrossRefPubMed

42.

Hirokawa K, Utsuyama M, Kasai M, Kurashima C, Ishijima S, Zeng YX (1994) Immunol Lett 40:269–277. https://doi.org/10.1016/0165-2478(94)00065-4CrossRefPubMed

43.

Thapa P, Farber DL (2019) The role of the thymus in the immune response. Thorac Surg Clin 29:123–131. https://doi.org/10.1016/j.thorsurg.2018.12.001CrossRefPubMedPubMedCentral

44.

Thomas R, Wang W, Su DM (2020) Contributions of age-related thymic involution to immunosenescence and inflammaging. Immun Ageing 17:2. https://doi.org/10.1186/s12979-020-0173-8.6CrossRefPubMedPubMedCentral

45.

Pawelec G, Barnett Y, Forsey R, Frasca D, Globerson A, McLeod J, Caruso C, Franceschi C, Fülöp T, Gupta S, Mariani E, Mocchegiani E, Solana R (2002) T cells and aging, January 2002 update. Front Biosci 1(7):d1056–d1183. https://doi.org/10.2741/a831CrossRef

46.

Qi Q, Liu Y, Cheng Y, Glanville J, Zhang D, Lee JY, Olshen RA, Weyand CM, Boyd SD, Goronzy JJ (2014) Diversity and clonal selection in the human T-cell repertoire. Proc Natl Acad Sci U S A 111:13139–13144. https://doi.org/10.1073/pnas.1409155111CrossRefPubMedPubMedCentral

47.

Di Benedetto S, Derhovanessian E, Steinhagen-Thiessen E, Goldeck D, Müller L, Pawelec G (2015) Impact of age, sex and CMV-infection on peripheral T cell phenotypes: results from the Berlin BASE-II Study. Biogerontology 16:631–643. https://doi.org/10.1007/s10522-015-9563-2CrossRefPubMed

48.

Frasca D, Blomberg BB (2016) Inflammaging decreases adaptive and innate immune responses in mice and humans. Biogerontology 17(1):7–19. https://doi.org/10.1007/s10522-015-9578-8CrossRefPubMed

49.

Castelo-Branco C, Soveral I (2014) The immune system and aging: a review. Gynecol Endocrinol 30(1):16–22. https://doi.org/10.3109/09513590.2013.852531CrossRefPubMed

50.

Pawelec G (2018) Age and immunity: what is “immunosenescence”? Exp Gerontol 105:4–9. https://doi.org/10.1016/j.exger.2017.10.024CrossRefPubMed

51.

Pera A, Campos C, López N, Hassouneh F, Alonso C, Tarazona R, Solana R (2015) Immunosenescence: implications for response to infection and vaccination in older people. Maturitas 82:50–55. https://doi.org/10.1016/j.maturitas.2015.05.004CrossRefPubMed

52.

Gustafson CE, Kim C, Weyand CM, Goronzy JJ (2020) J Allergy Clin Immunol 145:1309–1321. https://doi.org/10.1016/j.jaci.2020.03.017CrossRefPubMedPubMedCentral

53.

Andrew MK, Bowles SK, Pawelec G, Haynes L, Kuchel GA, McNeil SA, McElhaney JE (2019) Influenza vaccination in older adults: recent innovations and practical applications. Drugs Aging 36:29–37. https://doi.org/10.1007/s40266-018-0597-4CrossRefPubMed

54.

Wagner A, Weinberger B (2020) Vaccines to prevent infectious diseases in the older population: immunological challenges and future perspectives. Front Immunol 11:717. https://doi.org/10.3389/fimmu.2020.00717CrossRefPubMedPubMedCentral

55.

Lal H, Cunningham AL, Godeaux O, Chlibek R, Diez-Domingo J, Hwang SJ, Levin MJ, McElhaney JE, Poder A, Puig-Barberà J, Vesikari T, Watanabe D, Weckx L, Zahaf T, Heineman TC, ZOE-50 Study Group (2015) Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med 372:2087–2096. https://doi.org/10.1056/NEJMoa1501184CrossRef

56.

de Waure C, Boccalini S, Bonanni P, Amicizia D, Poscia A, Bechini A, Barbieri M, Capri S, Specchia ML, Di Pietro ML, Arata L, Cacciatore P, Panatto D, Gasparini R (2019) Adjuvanted influenza vaccine for the Italian elderly in the 2018/19 season: an updated health technology assessment. Eur J Public Health 29:900–905. https://doi.org/10.1093/eurpub/ckz041CrossRefPubMedPubMedCentral

57.

Vallejo AN (2006) Age-dependent alterations of the T cell repertoire and functional diversity of T cells of the aged. Immunol Res 36:221–228. https://doi.org/10.1385/IR:36:1:221CrossRefPubMed

58.

Goronzy JJ, Fang F, Cavanagh MM, Qi Q, Weyand CM (2015) Naive T cell maintenance and function in human aging. J Immunol 194:4073–4080. https://doi.org/10.4049/jimmunol.1500046CrossRefPubMed

59.

Weyand CM, Goronzy JJ (2016) Aging of the immune system. Mechanisms and therapeutic targets. Ann Am Thorac Soc S422-S428. 13 Suppl 5(Suppl 5). https://doi.org/10.1513/AnnalsATS.201602-095AW

60.

Qi Q, Zhang DW, Weyand CM, Goronzy JJ (2014) Mechanisms shaping the naive T cell repertoire in the elderly - thymic involution or peripheral homeostatic proliferation? Exp Gerontol 54:71–74. https://doi.org/10.1016/j.exger.2014.01.005CrossRefPubMedPubMedCentral

61.

Franceschi C, Salvioli S, Garagnani P, de Eguileor M, Monti D, Capri M (2017) Immunobiography and the heterogeneity of immune responses in the elderly: a focus on inflammaging and trained immunity. Front Immunol 8:982. https://doi.org/10.3389/fimmu.2017.00982CrossRefPubMedPubMedCentral

62.

Fulop T, Larbi A, Hirokawa K, Cohen AA, Witkowski JM (2020) Immunosenescence is both functional/adaptive and dysfunctional/maladaptive. Semin Immunopathol 42:521–536. https://doi.org/10.1007/s00281-020-00818-9CrossRefPubMedPubMedCentral

63.

Vitlic A, Lord JM, Phillips AC (2014) Stress, ageing and their influence on functional, cellular and molecular aspects of the immune system. Age (Dordr) 36:9631. https://doi.org/10.1007/s11357-014-9631CrossRefPubMed

64.

Goldberg EL, Shaw AC, Montgomery RR (2020) How inflammation blunts innate immunity in aging. Interdiscip Top Gerontol Geriatr 43:1–17. https://doi.org/10.1159/000504480CrossRefPubMedPubMedCentral

65.

Franceschi C, Garagnani P, Vitale G, Capri M, Salvioli S (2017) Inflammaging and ‘Garb-aging.’ Trends Endocrinol Metab 28:199–212. https://doi.org/10.1016/j.tem.2016.09.005CrossRefPubMed

66.

Callender LA, Carroll EC, Beal RWJ, Chambers ES, Nourshargh S, Akbar AN, Henson SM (2018) Human CD8+ EMRA T cells display a senescence-associated secretory phenotype regulated by p38 MAPK. Aging Cell 17:e12675. https://doi.org/10.1111/acel.12675CrossRefPubMed

67.

Xu W, Larbi A (2017) Markers of T cell senescence in humans. Int J Mol Sci 18:1742. https://doi.org/10.3390/ijms18081742CrossRefPubMedPubMedCentral

68.

Chou JP, Effros RB (2013) T cell replicative senescence in human aging. Curr Pharm Des 19:1680–1698. https://doi.org/10.2174/138161213805219711CrossRefPubMedPubMedCentral

69.

Fülöp T, Larbi A, Pawelec G (2013) Human T cell aging and the impact of persistent viral infections. Front Immunol 4:271. https://doi.org/10.3389/fimmu.2013.00271CrossRefPubMedPubMedCentral

70.

Witkowski JM, Mikosik A, Bryl E, Fulop T (2018) Proteodynamics in aging human T cells - the need for its comprehensive study to understand the fine regulation of T lymphocyte functions. Exp Gerontol 107:161–168. https://doi.org/10.1016/j.exger.2017.10.009CrossRefPubMed

71.

Mayya V, Judokusumo E, Abu-Shah E, Neiswanger W, Sachar C, Depoil D, Kam LC, Dustin ML (2019) Cutting edge: synapse propensity of human memory CD8 T cells confers competitive advantage over naive counterparts. J Immunol 203:601–606. https://doi.org/10.4049/jimmunol.1801687CrossRefPubMedPubMedCentral

72.

Larbi A, Dupuis G, Khalil A, Douziech N, Fortin C, Fülöp T Jr (2006) Differential role of lipid rafts in the functions of CD4+ and CD8+ human T lymphocytes with aging. Cell Signal 18:1017–1030. https://doi.org/10.1016/j.cellsig.2005.08.016CrossRefPubMed

73.

Fulop T, Le Page A, Garneau H, Azimi N, Baehl S, Dupuis G, Pawelec G, Larbi A (2012) Aging, immunosenescence and membrane rafts: the lipid connection. Longev Healthspan 1:6. https://doi.org/10.1186/2046-2395-1-6CrossRefPubMedPubMedCentral

74.

Ohno-Iwashita Y, Shimada Y, Hayashi M, Inomata M (2010) Plasma membrane microdomains in aging and disease. Geriatr Gerontol Int 10(Suppl 1):S41-52. https://doi.org/10.1111/j.1447-0594.2010.00600.xCrossRefPubMed

75.

Gupta SS (1989) Membrane signal transduction in T cells in aging humans. Ann N Y Acad Sci 568:277–282. https://doi.org/10.1111/j.1749-6632.1989.tb12517.xCrossRefPubMed

76.

Fulop T, Le Page A, Fortin C, Witkowski JM, Dupuis G, Larbi A (2014) Cellular signaling in the aging immune system. Curr Opin Immunol 29:105–111. https://doi.org/10.1016/j.coi.2014.05.007CrossRefPubMed

77.

Le Page A, Dupuis G, Larbi A, Witkowski JM, Fülöp T (2018) Signal transduction changes in CD4(+) and CD8(+) T cell subpopulations with aging. Exp Gerontol 105:128–139. https://doi.org/10.1016/j.exger.2018.01.005CrossRefPubMed

78.

Vallejo AN (2005) CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol Rev 205:158–169. https://doi.org/10.1111/j.0105-2896.2005.00256.xCrossRefPubMed

79.

McGuire PJ (2019) Mitochondrial dysfunction and the aging immune system. Biology (Basel) 8:26. https://doi.org/10.3390/biology8020026CrossRefPubMed

80.

Lee KA, Robbins PD, Camell CD (2021) Intersection of immunometabolism and immunosenescence during aging. Curr Opin Pharmacol 57:107–116. https://doi.org/10.1016/j.coph.2021.01.003CrossRefPubMedPubMedCentral

81.

Pearce EL, Pearce EJ (2013) Metabolic pathways in immune cell activation and quiescence. Immunity 38:633–643. https://doi.org/10.1016/j.immuni.2013.04.005CrossRefPubMedPubMedCentral

82.

Nicoli F, Papagno L, Frere JJ, Cabral-Piccin MP, Clave E, Gostick E, Toubert A, Price DA, Caputo A, Appay V (2018) Front Immunol 9:2736. https://doi.org/10.3389/fimmu.2018.02736CrossRefPubMedPubMedCentral

83.

Yanes RE, Zhang H, Shen Y, Weyand CM, Goronzy JJ (2019) Metabolic reprogramming in memory CD4 T cell responses of old adults. Clin Immunol 207:58–67. https://doi.org/10.1016/j.clim.2019.07.003CrossRefPubMedPubMedCentral

84.

Liu GY, Sabatini DM (2020) mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol 21:183–203. https://doi.org/10.1038/s41580-019-0199-yCrossRefPubMedPubMedCentral

85.

Bjedov I, Rallis C (2020) The target of rapamycin signalling pathway in ageing and lifespan regulation. Genes (Basel) 11:1043. https://doi.org/10.3390/genes11091043CrossRefPubMed

86.

Ottaviani E, Franceschi C (1997) The invertebrate phagocytic immunocyte: clues to a common evolution of the immune and the endocrine systems. Immunol Today 18:169–174CrossRefPubMed

87.

Teti G, Biondo C, Beninati C (2016) The phagocyte, Metchnikoff, and the foundation of immunology. Microbiol Spectr 4(2). https://doi.org/10.1128/microbiolspec.MCHD-0009-2015

88.

Underhill DM, Gordon S, Imhof BA, Núñez G, Bousso P (2016) Elie Metchnikoff (1845–1916): celebrating 100 years of cellular immunology and beyond. Nat Rev Immunol 16:651–656. https://doi.org/10.1038/nri.2016.89CrossRefPubMed

89.

Beutler B (2004) Innate immunity: an overview. Mol Immunol 40(12):845–859. https://doi.org/10.1016/j.molimm.2003.10.005CrossRefPubMed

90.

Ebihara T (2020) Dichotomous regulation of acquired immunity by innate lymphoid cells. Cells 9:1193. https://doi.org/10.3390/cells9051193CrossRefPubMedPubMedCentral

91.

Rosales C (2020) Neutrophils at the crossroads of innate and adaptive immunity. J Leukoc Biol 108:377–396. https://doi.org/10.1002/JLB.4MIR0220-574RRCrossRefPubMed

92.

Locati M, Curtale G, Mantovani A (2020) Diversity, mechanisms, and significance of macrophage plasticity. Annu Rev Pathol 15:123–147. https://doi.org/10.1146/annurev-pathmechdis-012418-012718CrossRefPubMed

93.

Bi J, Wang X (2020) Molecular regulation of NK cell maturation. Front Immunol 11:1945. https://doi.org/10.3389/fimmu.2020.01945CrossRefPubMedPubMedCentral

94.

Riera Romo M, Pérez-Martínez D, Castillo FC (2016) Innate immunity in vertebrates: an overview. Immunology 148:125–139. https://doi.org/10.1111/imm.12597CrossRefPubMedPubMedCentral

95.

Ottaviani E, Malagoli D, Capri M, Franceschi C (2008) Ecoimmunology: is there any room for the neuroendocrine system? BioEssays 30(9):868–874. https://doi.org/10.1002/bies.20801CrossRefPubMed

96.

Fulop T, Dupuis G, Baehl S, Le Page A, Bourgade K, Frost E, Witkowski JM, Pawelec G, Larbi A, Cunnane S (2016) From inflamm-aging to immune-paralysis: a slippery slope during aging for immune-adaptation. Biogerontology 17:147–157. https://doi.org/10.1007/s10522-015-9615-7CrossRefPubMed

97.

Hearps AC, Martin GE, Angelovich TA, Cheng WJ, Maisa A, Landay AL, Jaworowski A, Crowe SM (2012) Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. Aging Cell 11(5):867–875. https://doi.org/10.1111/j.1474-9726.2012.00851.xCrossRefPubMed

98.

Nyugen J, Agrawal S, Gollapudi S, Gupta S (2010) Impaired functions of peripheral blood monocyte subpopulations in aged humans. J Clin Immunol 30(6):806–813. https://doi.org/10.1007/s10875-010-9448-8CrossRefPubMedPubMedCentral

99.

De Maeyer RPH, Chambers ES (2021) The impact of ageing on monocytes and macrophages. Immunol Lett 230:1–10. https://doi.org/10.1016/j.imlet.2020.12.003CrossRefPubMed

100.

Merino A, Buendia P, Martin-Malo A, Aljama P, Ramirez R, Carracedo J (2011) Senescent CD14+CD16+ monocytes exhibit proinflammatory and proatherosclerotic activity. J Immunol 186(3):1809–1815. https://doi.org/10.4049/jimmunol.1001866CrossRefPubMed

101.

Ong SM, Hadadi E, Dang TM, Yeap WH, Tan CT, Ng TP, Larbi A, Wong SC (2018) The pro-inflammatory phenotype of the human non-classical monocyte subset is attributed to senescence. Cell Death Dis 9(3):266. https://doi.org/10.1038/s41419-018-0327-1CrossRefPubMedPubMedCentral

102.

Tarazona R, Campos C, Pera A, Sanchez-Correa B, Solana R (2015) Flow cytometry analysis of NK cell phenotype and function in aging. Methods Mol Biol 1343:9–18. https://doi.org/10.1007/978-1-4939-2963-4_2CrossRefPubMed

103.

Solana R, Campos C, Pera A, Tarazona R (2014) Shaping of NK cell subsets by aging. Curr Opin Immunol 29:56–61. https://doi.org/10.1016/j.coi.2014.04.002CrossRefPubMed

104.

Gupta S (2014) Role of dendritic cells in innate and adaptive immune response in human aging. Exp Gerontol 54:47–52. https://doi.org/10.1016/j.exger.2013.12.009CrossRefPubMed

105.

Gong T, Liu L, Jiang W, Zhou R (2020) DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat Rev Immunol 20:95–112. https://doi.org/10.1038/s41577-019-0215-7CrossRefPubMed

106.

Ablasser A, Hur S (2020) Regulation of cGAS- and RLR-mediated immunity to nucleic acids. Nat Immunol 21:17–29. https://doi.org/10.1038/s41590-019-0556-1CrossRefPubMed

107.

Fitzgerald KA, Kagan JC (2020) Toll-like receptors and the control of immunity. Cell 180:1044–1066. https://doi.org/10.1016/j.cell.2020.02.041CrossRefPubMedPubMedCentral

108.

Kumar H, Kawai T, Akira S (2011) Pathogen recognition by the innate immune system. Int Rev Immunol 30:16–34. https://doi.org/10.3109/08830185.2010.529976CrossRefPubMed

109.

Brown J, Wang H, Hajishengallis GN, Martin M (2011) TLR-signaling networks: an integration of adaptor molecules, kinases, and cross-talk. J Dent Res 90:417–427. https://doi.org/10.1177/0022034510381264CrossRefPubMedPubMedCentral

110.

Zhou Y, He C, Wang L, Ge B (2017) Post-translational regulation of antiviral innate signaling. Eur J Immunol 47:1414–1426. https://doi.org/10.1002/eji.201746959CrossRefPubMedPubMedCentral

111.

Shaw AC, Goldstein DR, Montgomery RR (2013) Age-dependent dysregulation of innate immunity. Nat Rev Immunol 13(12):875–887. https://doi.org/10.1038/nri3547CrossRefPubMedPubMedCentral

112.

Bailey KL, Smith LM, Heires AJ, Katafiasz DM, Romberger DJ, LeVan TD (2019) Aging leads to dysfunctional innate immune responses to TLR2 and TLR4 agonists. Aging Clin Exp Res 31:1185–1193. https://doi.org/10.1007/s40520-018-1064-0CrossRefPubMed

113.

Fülöp T, Larbi A, Witkowski JM (2019) Human inflammaging. Gerontology 65:495–504. https://doi.org/10.1159/000497375CrossRefPubMed

114.

Fortin CF, Larbi A, Lesur O, Douziech N, Fulop T Jr (2006) Impairment of SHP-1 down-regulation in the lipid rafts of human neutrophils under GM-CSF stimulation contributes to their age-related, altered functions. J Leukoc Biol 79:1061–1072. https://doi.org/10.1189/jlb.0805481CrossRefPubMed

115.

Netea MG, Domínguez-Andrés J, Barreiro LB, Chavakis T, Divangahi M, Fuchs E, Joosten LAB, van der Meer JWM, Mhlanga MM, Mulder WJM, Riksen NP, Schlitzer A, Schultze JL, Stabell Benn C, Sun JC, Xavier RJ, Latz E (2020) Defining trained immunity and its role in health and disease. Nat Rev Immunol 20:375–388. https://doi.org/10.1038/s41577-020-0285-6CrossRefPubMedPubMedCentral

116.

Kleinnijenhuis J, Quintin J, Preijers F, Joosten LA, Ifrim DC, Saeed S, Jacobs C, van Loenhout J, de Jong D, Stunnenberg HG, Xavier RJ, van der Meer JW, van Crevel R, Netea MG (2012) Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A 109:17537–17542CrossRefPubMedPubMedCentral

117.

Domínguez-Andrés J, Fanucchi S, Joosten LAB, Mhlanga MM, Netea MG (2020) Advances in understanding molecular regulation of innate immune memory. Curr Opin Cell Biol 63:68–75CrossRefPubMed

118.

Ciarlo E, Heinonen T, Théroude C, Asgari F, Le Roy D, Netea MG, Roger T (2019) Trained immunity confers broad-spectrum protection against bacterial infections. J Infect Dis pii: jiz692

119.

van der Heijden CDCC, Noz MP, Joosten LAB, Netea MG, Riksen NP, Keating ST (2017) Epigenetics and trained immunity. Antioxid Redox Signal 29(11):1023–1040CrossRefPubMed

120.

Arts RJ, Joosten LA, Netea MG (2016) Immunometabolic circuits in trained immunity. Semin Immunol 28:425–430CrossRefPubMed

121.

Franceschi C (1989) Cell proliferation, cell death and aging. Aging 1:3–15. https://doi.org/10.1007/BF03323871CrossRefPubMed

122.

Kirkwood TB, Franceschi C (1992) Is aging as complex as it would appear? New perspectives in aging research. Ann N Y Acad Sci 21(663):412–417. https://doi.org/10.1111/j.1749-6632.1992.tb38685.xCrossRef

123.

Son DH, Park WJ, Lee YJ (2019) Recent advances in anti-aging medicine. Korean J Fam Med 40:289–296. https://doi.org/10.4082/kjfm.19.0087CrossRefPubMedPubMedCentral

124.

Chatterjee A, Georgiev G, Iannacchione G (2017) Aging and efficiency in living systems: complexity, adaptation and self-organization. Mech Ageing Dev 163:2–7. https://doi.org/10.1016/j.mad.2017.02.009CrossRefPubMed

125.

Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128:92–105. https://doi.org/10.1016/j.mad.2006.11.016CrossRefPubMed

126.

Giunta S (2008) Exploring the complex relations between inflammation and aging (inflamm-aging): anti-inflamm-aging remodelling of inflamm-aging, from robustness to frailty. Inflamm Res 57(12):558–563. https://doi.org/10.1007/s00011-008-7243-2CrossRefPubMed

127.

Morrisette-Thomas V, Cohen AA, Fülöp T, Riesco É, Legault V, Li Q, Milot E, Dusseault-Bélanger F, Ferrucci L (2014) Inflamm-aging does not simply reflect increases in pro-inflammatory markers. Mech Ageing Dev 139:49–57. https://doi.org/10.1016/j.mad.2014.06.005CrossRefPubMedPubMedCentral

128.

Ottaviani E, Franceschi C (1997) The invertebrate phagocytic immunocyte: clues to a common evolution of immune and neuroendocrine systems. Immunol Today 18(4):169–174. https://doi.org/10.1016/s0167-5699(97)84663-4CrossRefPubMed

129.

Ottaviani E, Franceschi C (1998) A new theory on the common evolutionary origin of natural immunity, inflammation and stress response: the invertebrate phagocytic immunocyte as an eye-witness. Domest Anim Endocrinol 15(5):291–296. https://doi.org/10.1016/s0739-7240(98)00021-6CrossRefPubMed

130.

Martucci M, Ostan R, Biondi F, Bellavista E, Fabbri C, Bertarelli C, Salvioli S, Capri M, Franceschi C, Santoro A (2017) Mediterranean diet and inflammaging within the hormesis paradigm. Nutr Rev 75(6):442–455. https://doi.org/10.1093/nutrit/nux013CrossRefPubMedPubMedCentral

131.

Santoro A, Martucci M, Conte M, Capri M, Franceschi C, Salvioli S (2020) Inflammaging, hormesis and the rationale for anti-aging strategies. Ageing Res Rev 64:101142. https://doi.org/10.1016/j.arr.2020.101142CrossRefPubMed

132.

Selye H (1950) Stress and the general adaptation syndrome. Br Med J 1(4667):1383–1392. https://doi.org/10.1136/bmj.1.4667.1383CrossRefPubMedPubMedCentral

133.

Franceschi C, Valensin S, Fagnoni F, Barbi C, Bonafè M (1999) Biomarkers of immunosenescence within an evolutionary perspective: the challenge of heterogeneity and the role of antigenic load. Exp Gerontol 34(8):911–921. https://doi.org/10.1016/s0531-5565(99)00068-6CrossRefPubMed

134.

Hitt R, Young-Xu Y, Silver M, Perls T (1999) Centenarians: the older you get, the healthier you have been. Lancet 354(9179):652. https://doi.org/10.1016/S0140-6736(99)01987-XCrossRefPubMed

135.

Franceschi C, Monti D, Sansoni P, Cossarizza A (1995) The immunology of exceptional individuals: the lesson of centenarians. Immunol Today 16:12–16. https://doi.org/10.1016/0167-5699(95)80064-6CrossRefPubMed

136.

Santos-Lozano A, Valenzuela PL, Llavero F, Lista S, Carrera-Bastos P, Hampel H, Pareja-Galeano H, Gálvez BG, López JA, Vázquez J, Emanuele E, Zugaza JL, Lucia A (2020) Successful aging: insights from proteome analyses of healthy centenarians. Aging (Albany NY) 12:3502–3515. https://doi.org/10.18632/aging.102826CrossRefPubMed

137.

Caruso C, Aiello A, Accardi G, Ciaglia E, Cattaneo M, Puca A (2019) Genetic signatures of centenarians: implications for achieving successful aging. Curr Pharm Des 25:4133–4138. https://doi.org/10.2174/1381612825666191112094544CrossRefPubMed

138.

Johnson TE, Bruunsgaard H (1998) Implications of hormesis for biomedical aging research. Hum Exp Toxicol 17(5):263–265. https://doi.org/10.1177/096032719801700509CrossRefPubMed

139.

Calabrese EJ, Baldwin LA (1999) The marginalization of hormesis. Toxicol Pathol 27(2):187–94. https://doi.org/10.1177/019262339902700206

140.

Franceschi C, Garagnani P, Morsiani C, Conte M, Santoro A, Grignolio A, Monti D, Capri M, Salvioli S (2018) The continuum of aging and age-related diseases: common mechanisms but different rates. Front Med (Lausanne) 5:61. https://doi.org/10.3389/fmed.2018.00061CrossRefPubMed

141.

Giuliani C, Pirazzini C, Delledonne M, Xumerle L, Descombes P, Marquis J, Mengozzi G, Monti D, Bellizzi D, Passarino G, Luiselli D, Franceschi C, Garagnani P (2017) Centenarians as extreme phenotypes: an ecological perspective to get insight into the relationship between the genetics of longevity and age-associated diseases. Mech Ageing Dev 165(Pt B):195–201. https://doi.org/10.1016/j.mad.2017.02.007CrossRefPubMed

142.

Fagiolo U, Cossarizza A, Scala E, Fanales-Belasio E, Ortolani C, Cozzi E, Monti D, Franceschi C, Paganelli R (1993) Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol 23(9):2375–2378. https://doi.org/10.1002/eji.1830230950CrossRefPubMed

143.

Baggio G, Donazzan S, Monti D, Mari D, Martini S, Gabelli C, Dalla Vestra M, Previato L, Guido M, Pigozzo S, Cortella I, Crepaldi G, Franceschi C (1998) Lipoprotein(a) and lipoprotein profile in healthy centenarians: a reappraisal of vascular risk factors. FASEB J 12(6):433–437. https://doi.org/10.1096/fasebj.12.6.433CrossRefPubMed

144.

Arai Y, Martin-Ruiz CM, Takayama M, Abe Y, Takebayashi T, Koyasu S, Suematsu M, Hirose N, von Zglinicki T (2015) Inflammation, but not telomere length, predicts successful ageing at extreme old age: a longitudinal study of semi-supercentenarians. EBioMedicine 2(10):1549–1558. https://doi.org/10.1016/j.ebiom.2015.07.029CrossRefPubMedPubMedCentral

145.

Franceschi C, Bonafè M, Valensin S (2000) Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space. Vaccine 18(16):1717–1720. https://doi.org/10.1016/s0264-410x(99)00513-7CrossRefPubMed

146.

Olivieri F, Albertini MC, Orciani M, Ceka A, Cricca M, Procopio AD, Bonafè M (2015) DNA damage response (DDR) and senescence: shuttled inflamma-miRNAs on the stage of inflamm-aging. Oncotarget 6:35509–35521CrossRefPubMedPubMedCentral

147.

Effros RB (2003) Replicative senescence: the final stage of memory T cell differentiation? Curr HIV Res 1:153–165CrossRefPubMed

148.

Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J (2018) Senescence-associated secretory phenotypes reveal cell- nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6:2853–2868

149.

Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL (2013) Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest 123:966–972CrossRefPubMedPubMedCentral

150.

Birch J, Passos JF (2017) Targeting the SASP to combat ageing: mitochondria as possible intracellular allies? Bioessays 39(5)

151.

Campisi J (2016) Cellular senescence and lung function during aging. Yin and Yang. Ann Am Thorac Soc 13(Supplement_5):S402

152.

Yarbro JR, Emmons RS, Pence BD (2020) Macrophage immunometabolism and inflammaging: roles of mitochondrial dysfunction, cellular senescence, CD38, and NAD. Immunometabolism 2(3):e200026. https://doi.org/10.20900/immunometab20200026CrossRefPubMedPubMedCentral

153.

Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621. https://doi.org/10.1016/0014-4827(61)90192-6CrossRefPubMed

154.

155.

Iske J, Seyda M, Heinbokel T, Maenosono R, Minami K, Nian Y, Quante M, Falk CS, Azuma H, Martin F, Passos JF, Niemann CU, Tchkonia T, Kirkland JL, Elkhal A, Tullius SG (2020) Senolytics prevent mt-DNA-induced inflammation and promote the survival of aged organs following transplantation. Nat Commun 11(1):4289. https://doi.org/10.1038/s41467-020-18039-xCrossRefPubMedPubMedCentral

156.

Olivieri F, Prattichizzo F, Grillari J, Balistreri CR (2018) Cellular senescence and inflammaging in age-related diseases. Mediators Inflamm 17(2018):9076485. https://doi.org/10.1155/2018/9076485CrossRef

157.

Bektas A, Schurman SH, Sen R, Ferrucci L (2017) Human T cell immunosenescence and inflammation in aging. J Leukoc Biol 102(4):977–988. https://doi.org/10.1189/jlb.3RI0716-335RCrossRefPubMedPubMedCentral

158.

Schmeer C, Kretz A, Wengerodt D, Stojiljkovic M, Witte OW (2019) Dissecting aging and senescence-current concepts and open lessons. Cells 8(11):1446. https://doi.org/10.3390/cells8111446CrossRefPubMedPubMedCentral

159.

Santoro A, Zhao J, Wu L, Carru C, Biagi E, Franceschi C (2020) Microbiomes other than the gut: inflammaging and age-related diseases. Semin Immunopathol 42:589–605. https://doi.org/10.1007/s00281-020-00814-zCrossRefPubMedPubMedCentral

160.

Peterson CT, Sharma V, Elmén L, Peterson SN (2015) Immune homeostasis, dysbiosis and therapeutic modulation of the gut microbiota. Clin Exp Immunol 179(3):363–377. https://doi.org/10.1111/cei.12474CrossRefPubMedPubMedCentral

161.

Biagi E, Candela M, Turroni S, Garagnani P, Franceschi C, Brigidi P (2013) Ageing and gut microbes: perspectives for health maintenance and longevity. Pharmacol Res 69(1):11–20CrossRefPubMed

162.

Bosco N, Noti M (2021) The aging gut microbiome and its impact on host immunity. Genes Immun 19:1–15. https://doi.org/10.1038/s41435-021-00126-8CrossRef

163.

Ragonnaud E, Biragyn A (2021) Gut microbiota as the key controllers of “healthy” aging of elderly people. Immun Ageing 18(1):2. https://doi.org/10.1186/s12979-020-00213-wCrossRefPubMedPubMedCentral

164.

DeJong EN, Surette MG, Bowdish DME (2020) The gut microbiota and unhealthy aging: disentangling cause from consequence. Cell Host Microbe 28(2):180–189. https://doi.org/10.1016/j.chom.2020.07.013CrossRefPubMed

165.

Franceschi C, Ostan R, Santoro A (2018) Nutrition and inflammation: are centenarians similar to individuals on calorie-restricted diets? Annu Rev Nutr 21(38):329–356. https://doi.org/10.1146/annurev-nutr-082117-051637CrossRef

166.

Biagi E, Franceschi C, Rampelli S, Severgnini M, Ostan R, Turroni S, Consolandi C, Quercia S, Scurti M, Monti D, Capri M, Brigidi P, Candela M (2016) Gut microbiota and extreme longevity. Curr Biol 26(11):1480–1485. https://doi.org/10.1016/j.cub.2016.04.016CrossRefPubMed

167.

Santoro A, Ostan R, Candela M, Biagi E, Brigidi P, Capri M, Franceschi C (2018) Gut microbiota changes in the extreme decades of human life: a focus on centenarians. Cell Mol Life Sci 75(1):129–148. https://doi.org/10.1007/s00018-017-2674-yCrossRefPubMed

168.

Coman V, Vodnar DC (2020) Gut microbiota and old age: modulating factors and interventions for healthy longevity. Exp Gerontol 41:111095. https://doi.org/10.1016/j.exger.2020.111095CrossRef

169.

Bulut O, Kilic G, Domínguez-Andrés J, Netea MG (2020) Overcoming immune dysfunction in the elderly: trained immunity as a novel approach. Int Immunol 32(12):741–753. https://doi.org/10.1093/intimm/dxaa052CrossRefPubMedPubMedCentral

170.

Chapman J, Fielder E, Passos JF (2019) Mitochondrial dysfunction and cell senescence: deciphering a complex relationship. FEBS Lett 593:1566–1579. https://doi.org/10.1002/1873-3468.13498CrossRefPubMed

171.

Omarjee L, Perrot F, Meilhac O, Mahe G, Bousquet G, Janin A (2020) Immunometabolism at the cornerstone of inflammaging, immunosenescence, and autoimmunity in COVID-19. Aging (Albany NY) 12:26263–26278. https://doi.org/10.18632/aging.202422CrossRefPubMed

172.

Salvioli S, Capri M, Valensin S, Tieri P, Monti D, Ottaviani E, Franceschi C (2006) Inflamm-aging, cytokines and aging: state of the art, new hypotheses on the role of mitochondria and new perspectives from systems biology. Curr Pharm Des 12(24):3161–3171. https://doi.org/10.2174/138161206777947470CrossRefPubMed

173.

Picca A, Lezza AMS, Leeuwenburgh C, Pesce V, Calvani R, Landi F, Bernabei R, Marzetti E (2017) Fueling inflamm-aging through mitochondrial dysfunction: mechanisms and molecular targets. Int J Mol Sci 18(5):933. https://doi.org/10.3390/ijms18050933CrossRefPubMedPubMedCentral

174.

Yang Q, Shu HB (2020) Deciphering the pathways to antiviral innate immunity and inflammation. Adv Immunol 145:1–36. https://doi.org/10.1016/bs.ai.2019.11.001CrossRefPubMed

175.

Burtscher J, Burtscher M, Millet GP (2021) The central role of mitochondrial fitness on antiviral defenses: an advocacy for physical activity during the COVID-19 pandemic. Redox Biol 43:101976. https://doi.org/10.1016/j.redox.2021.101976CrossRefPubMedPubMedCentral

176.

Conte M, Martucci M, Chiariello A, Franceschi C, Salvioli S (2020) Mitochondria, immunosenescence and inflammaging: a role for mitokines? Semin Immunopathol 42:607–617. https://doi.org/10.1007/s00281-020-00813-0CrossRefPubMedPubMedCentral

177.

Aiello A, Farzaneh F, Candore G, Caruso C, Davinelli S, Gambino CM, Ligotti ME, Zareian N, Accardi G (2019) Immunosenescence and its hallmarks: how to oppose aging strategically? A review of potential options for therapeutic intervention. Front Immunol 10:2247. https://doi.org/10.3389/fimmu.2019.02247CrossRefPubMedPubMedCentral

178.

Pereira B, Xu XN, Akbar AN (2020) Targeting inflammation and immunosenescence to improve vaccine responses in the elderly. Front Immunol 11:583019. https://doi.org/10.3389/fimmu.2020.583019CrossRefPubMedPubMedCentral

179.

De la Fuente M, Miquel J (2009) An update of the oxidation-inflammation theory of aging: the involvement of the immune system in oxi-inflamm-aging. Curr Pharm Des 15(26):3003–3026. https://doi.org/10.2174/138161209789058110CrossRefPubMed

180.

Yabluchanskiy A, Ungvari Z, Csiszar A, Tarantini S (2018) Advances and challenges in geroscience research: an update. Physiol Int 105(4):298–308. https://doi.org/10.1556/2060.105.2018.4.32CrossRefPubMedPubMedCentral

181.

Sierra F, Kohanski R (2017) Geroscience and the trans-NIH Geroscience Interest Group. GSIG Geroscience 39(1):1–5. https://doi.org/10.1007/s11357-016-9954-6CrossRefPubMed

182.

Carrasco E, Gómez de Las Heras MM, Gabandé-Rodríguez E, Desdín-Micó G, Aranda JF, Mittelbrunn M (2021) The role of T cells in age-related diseases. Nat Rev Immunol. https://doi.org/10.1038/s41577-021-00557-4

183.

Rea IM, Gibson DS, McGilligan V, McNerlan SE, Alexander HD, Ross OA (2018) Age and age-related diseases: role of inflammation triggers and cytokines. Front Immunol 9:586. eCollection 2018. https://doi.org/10.3389/fimmu.2018.00586

184.

Gritsenko A, Green JP, Brough D, Lopez-Castejon G (2020) Mechanisms of NLRP3 priming in inflammaging and age related diseases. Cytokine Growth Factor Rev 55:15–25. https://doi.org/10.1016/j.cytogfr.2020.08.003CrossRefPubMedPubMedCentral

185.

De Winter G (2015) Aging as disease. Med Health Care Philos 18:237–243. https://doi.org/10.1007/s11019-014-9600-yCrossRefPubMed

186.

Janac S, Clarke B, Gems D (2017) Aging: natural or disease? A view from medical textbooks. In: Vaiserman AM (ed) Anti-aging drugs: from basic research to clinical practice. Royal Society of Chemistry, Cambridge (UK), p 2017

187.

Fulop T, Larbi A, Khalil A, Cohen AA, Witkowski JM (2019) Are we ill because we age? Front Physiol 18(10):1508. https://doi.org/10.3389/fphys.2019.01508CrossRef

188.

Fulop T, Larbi A, Dupuis G, Le Page A, Frost EH, Cohen AA, Witkowski JM, Franceschi C (2018) Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? Front Immunol 10(8):1960. https://doi.org/10.3389/fimmu.2017.01960CrossRef

189.

Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF (2020) The proximal origin of SARS-CoV-2. Nature Med 26:450–452CrossRefPubMed

190.

Perrotta F, Corbi G, Mazzeo G, Boccia M, Aronne L, D’Agnano V, Komici K, Mazzarella G, Parrella R, Bianco A (2020) COVID-19 and the elderly: insights into pathogenesis and clinical decision-making. Aging Clin Exp Res 32(8):1599–1608. https://doi.org/10.1007/s40520-020-01631-yCrossRefPubMedPubMedCentral

191.

Kadambari S, Klenerman P, Pollard AJ (2020) Why the elderly appear to be more severely affected by COVID-19: the potential role of immunosenescence and CMV. Rev Med Virol 30:e2144. https://doi.org/10.1002/rmv.2144CrossRefPubMedPubMedCentral

192.

Cunha LL, Perazzio SF, Azzi J, Cravedi P, Riella LV (2020) Remodeling of the immune response with aging: immunosenescence and its potential impact on COVID-19 immune response. Front Immunol 7(11):1748. https://doi.org/10.3389/fimmu.2020.01748CrossRef

193.

Pietrobon AJ, Teixeira FME, Sato MN (2020) Immunosenescence and inflammaging: risk factors of severe COVID-19 in older people. Front Immunol 27(11):579220. https://doi.org/10.3389/fimmu.2020.579220CrossRef

194.

Akbar AN, Gilroy DW (2020) Aging immunity may exacerbate COVID-19. Science 369(6501):256–257. https://doi.org/10.1126/science.abb0762CrossRefPubMed

195.

Flaherty GT, Hession P, Liew CH, Lim BCW, Leong TK, Lim V, Sulaiman LH (2020) COVID-19 in adult patients with pre-existing chronic cardiac, respiratory and metabolic disease: a critical literature review with clinical recommendations. Trop Dis Travel Med Vaccines 28(6):16. https://doi.org/10.1186/s40794-020-00118-yCrossRef

196.

Arsun B, Shepherd HS, Claudio F, Luigi F (2020) A public health perspective of aging: do hyper-inflammatory syndromes such as COVID-19, SARS, ARDS, cytokine storm syndrome, and post-ICU syndrome accelerate short- and long-term inflammaging? Immun Ageing 17:23. eCollection 2020. https://doi.org/10.1186/s12979-020-00196-8

197.

Ostan R, Monti D, Gueresi P, Bussolotto M, Franceschi C, Baggio G (2016) Gender, aging and longevity in humans: an update of an intriguing/neglected scenario paving the way to a gender-specific medicine. Clin Sci (Lond) 130(19):1711–1725. https://doi.org/10.1042/CS20160004CrossRefPubMed

198.

Monti D, Ostan R, Borelli V, Castellani G, Franceschi C (2017) Inflammaging and human longevity in the omics era. Mech Ageing Dev 165(Pt B):129–138. https://doi.org/10.1016/j.mad.2016.12.008CrossRefPubMed

199.

Moderbacher CR, Ramirez SI, Dan JM, Grifoni A, Hastie KM, Weiskopf D, Belanger S, Abbott RK, Kim C, Choi J, Kato Y, Crotty EG, Kim C, Rawlings SA, Mateus J, Tse LPV, Frazier A, Baric R, Peters B, Greenbaum J, Saphire EO, Smith DM, Sette A, Crotty S (2020) Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity. Cell 183(4):996–1012.e19. Epub 2020 Sep 16. https://doi.org/10.1016/j.cell.2020.09.038

200.

Zheng Y, Liu X, Le W, Xie L, Li H, Wen W, Wang S, Ma S, Huang Z, Ye J, Shi W, Ye Y, Liu Z, Song M, Zhang W, Han JJ, Belmonte JCI, Xiao C, Qu J, Wang H, Liu GH, Su W (2020) A human circulating immune cell landscape in aging and COVID-19. Protein Cell 11(10):740–770. https://doi.org/10.1007/s13238-020-00762-2

201.

Duggal NA, Niemiro G, Harridge SDR, Simpson RJ, Lord JM (2019) Can physical activity ameliorate immunosenescence and thereby reduce age-related multi-morbidity? Nat Rev Immunol 19:563–572. https://doi.org/10.1038/s41577-019-0177-9CrossRefPubMed

202.

Weyh C, Krüger K, Strasser B (2020) Physical activity and diet shape the immune system during aging. Nutrients 12(3):622. https://doi.org/10.3390/nu12030622CrossRefPubMedPubMedCentral

203.

Fuellen G, Liesenfeld O, Kowald A, Barrantes I, Bastian M, Simm A, Jansen L, Tietz-Latza A, Quandt D, Franceschi C, Walter M (2020) The preventive strategy for pandemics in the elderly is to collect in advance samples & data to counteract chronic inflammation (inflammaging. Ageing Res Rev 62:101091. https://doi.org/10.1016/j.arr.2020.101091CrossRefPubMedPubMedCentral

204.

Xia S, Zhang X, Zheng S, Khanabdali R, Kalionis B, Wu J, Wan W, Tai X (2016) An update on inflamm-aging: mechanisms, prevention, and treatment. J Immunol Res 2016:8426874. https://doi.org/10.1155/2016/8426874CrossRefPubMedPubMedCentral

205.

Calder PC, Bosco N, Bourdet-Sicard R, Capuron L, Delzenne N, Doré J, Franceschi C, Lehtinen MJ, Recker T, Salvioli S, Visioli F (2017) Health relevance of the modification of low grade inflammation in ageing (inflammageing) and the role of nutrition. Ageing Res Rev 40:95–119. https://doi.org/10.1016/j.arr.2017.09.001CrossRefPubMed

206.

Chen Y, Klein SL, Garibaldi BT, Li H, Wu C, Osevala NM, Li T, Margolick JB, Pawelec G, Leng SX (2021) Aging in COVID-19: Vulnerability, immunity and intervention. Ageing Res Rev 65:101205. https://doi.org/10.1016/j.arr.2020.101205CrossRefPubMed

207.

Horvath S, Raj K (2018) DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet 19(6):371–384. https://doi.org/10.1038/s41576-018-0004-3CrossRefPubMed

Title: Immunology of Aging: the Birth of Inflammaging
Authors: T. Fulop
A. Larbi
G. Pawelec
A. Khalil
A. A. Cohen
K. Hirokawa
J. M. Witkowski
C. Franceschi
Publication date: 18-09-2021
Publisher: Springer US
Keyword: Cytokines
Published in: Clinical Reviews in Allergy & Immunology / Issue 2/2023
Print ISSN: 1080-0549
Electronic ISSN: 1559-0267
DOI: https://doi.org/10.1007/s12016-021-08899-6

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STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

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